Motor neuron diseases include amyotrophic lateral sclerosis (ALS) in which both primary motor neurons and secondary motor neurons are damaged, and spinal muscle atrophy (SMA) in which only secondary motor neurons are damaged, and other diseases are known such as progressive bulbar palsy, primary lateral sclerosis (PLS), and arthrogryposis multiplex congenita (AMC). Of these, ALS often begins in late middle age, and is a lethal intractable disease, in which the condition rapidly deteriorates from muscular atrophy and muscle weakness to, finally, death due to respiratory insufficiency or the like in a matter of a few years. The cause and pathology of ALS have not been sufficiently elucidated.
Major causes of ALS that have been proposed as hypotheses are: (1) autoimmunity (the appearance of autoantibody against Ca channels), (2) excitatory amino acid excess/toxicity (increased extracellular glutamic acid and blocked transport of glutamic acid), (3) oxidative stress disorders (neuronopathy due to abnormality of Cu/Zn superoxide dismutase (SOD) gene and free radical), (4) cytoskeletal disorders (accumulation of neurofilaments in motor nerve cells and appearance of inclusions), and (5) deficiency of neurotrophic factors, and the like.
Among these hypothesized causes of ALS, based on the oxidative stress disorder hypothesis, whether or not antioxidants are effective against ALS has attracted attention. For example, a lecithinized SOD therapy had been attempted (Cranial Nerves 50(7): 615–624, 1998). However, it was shown that even when human recombinant Cu/Zn SOD was administered intraspinally to ALS patients, effective therapeutic effects were not obtained (Cranial Nerves 50(7): 615–624, 1998).
Further, riluzole (JP Patent Publication (PCT Translation) No. 7-504655) (trade name: Rilutek (Rhone-poulenc Rorer)) is known as an existing therapeutic agent for ALS. This therapeutic agent is a benzothiazole compound, which has been shown to suppress glutamic acid transmission in glutaminergic nerves, and have a neuroprotective effect against neurodegeneration. Clinical trials of this therapeutic agent against ALS are underway, and the agent has been approved as a medicament. However, some test results have been reported in which effectiveness against ALS could not be confirmed. The development of a more effective therapeutic agent for ALS has been desired.